Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39591—Stabilisation, fragmentation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

• the invention relates to the formulation of human immunoglobulin G, of use in therapy.
• IgG immunoglobulin G
• Mention may, for example, be made of primary immune deficiencies with an antibody production defect, Kawasaki disease, childhood and adult immune thrombocytopaenic purpura, secondary immune deficiencies with an antibody production defect, in particular chronic lymphoid leukaemia or myeloma that are associated with recurrent infections, HIV infection of children associated with bacterial infections, multifocal motor neuropathies, Guillain-Barré syndrome, chronic or severe acute Parvovirus B19 infections, acquired or constitutional immunodeficiency, cortico-resistant dermatomyositis, acute myasthenia, chronic idiopathic polyradiculoneuritis, immune thrombocytopaenic purpura, for example associated with HIV infection, stiff-person syndrome, autoimmune neutropaenia, resistant autoimmune erythroblastopenia, autoantibody-induced acquired anticoagulant syndrome, rheumatoid arthritis, uveitis, etc.
• Pathological conditions treated with immunoglobulins involve particularly high posologies which represent doses of about from 0.4 to 2 grams by body weight of the patient and per month.
• immunoglobulin G sold today is intended for intravenous administration, which allows infusions of several tens of grams of IgG in preparations of several hundred millimeters at a rate of one administration every three or four weeks.
• Intravenous administration requires the presence of care staff; it is most commonly carried out in hospital. In young children and the elderly, intravenous administration can be made difficult owing to a poor venous approach, which can, in certain cases, prevent access to the treatment.
• IgG intended for subcutaneous administration exists.
• This route of administration offers the patient greater flexibility and greater independence, improving the quality of life of patients.
• the use of subcutaneous immunoglobulins (SCIg) also reduces certain side effects associated with intravenous infusions, in particular the risk of systemic reactions.
• the large variation in circulating titres observed by the intravenous route are avoided via the subcutaneous route, allowing better regulation of the serum titre in the physiological range between infusions.
• SCIg One of the main limitations of the use of SCIg is the dose to be administered: it requires large volumes injected in one or more sites with a narrower frequency than IVIg, every two weeks or every week or even several times a week.
• the injection of large volumes with the commercial SCIg can cause local intolerance reactions such as oedema or erythema (M. Delire et al., “Expérience University de l'administration d'immunoglobulines par opposed sous-cuta dire dans le. des immunodéficiences primaires” [“Clinical experience of the subcutaneous administration of immunoglobulins in the treatment of primary immunodeficiencies”], Rev Med Liège 2010; 65:2; 103-108).
• the SCIg concentration is a determining characteristic which conditions the injection volume and the number of injection sites. Given the doses injected and the maximum injectable volume per site, the SCIg concentration defines the number of injection sites and consequently the frequency of administration.
• IgPro20® from Hizentra, which can be administered subcutaneously, is known.
• IgG solutions at 160 g/l or 16% which can be administered subcutaneously also exist, such as, in particular, Vivaglobulin® from Baxter or else Gammanorm® from Octapharma.
• oligomers and polymers can form in said composition.
• the oligomers and polymers are capable of activating the complement system with associated risks of anaphylactic reactions. These oligomers and polymers are also capable of inducing hypotension phenomena in the treated patient. This is not desirable and is strictly controlled from a regulatory point of view.
• the increase in viscosity associated with the IgG concentration is also a major technical constraint.
• the viscosity can in fact generate problems both in terms of the process for the formulation and aseptic distribution steps and in terms of the final application with respect to the syringability of the IgG composition.
• IgG compositions at highly elevated concentrations so as to reduce the injection volume thereof, which can be easily administered and are well tolerated for subcutaneous administration, from for example human plasma, making it possible to improve patient comfort and to reduce side effects.
• the Applicant has developed a new process for obtaining highly concentrated IgG compositions, at at least 230 g/l, more generally between 230 and 350 g/l, which are easy to administer subcutaneously.
• the new process makes it possible to obtain concentrated IgG compositions at at least 250 g/l, preferably from approximately 250 g/l to approximately 300 g/l.
• the process for preparing a pharmaceutical composition comprising human immunoglobulin G comprises the following steps:
• One or more compounds chosen from sugars, sugar derivatives and salts can also be added in step b).
• the novel process for preparing a pharmaceutical composition comprising human immunoglobulin G comprises the following steps:
• step b) of the process according to the invention the amino acids, sugars, sugar derivatives, salts and/or surfactants at a concentration below the critical micellar concentration of said surfactants
• step b) of the process according to the invention the amino acids, sugars, sugar derivatives, salts and/or surfactants at a concentration below the critical micellar concentration of said surfactants
• At least one amino acid which may be a hydrophilic amino acid or an amino acid bearing a positively charged side chain, is added in step b) of the process for preparing a liquid pharmaceutical composition.
• At least one amino acid said amino acid being a hydrophilic amino acid or an amino acid bearing a positively charged side chain, combined with at least one hydrophobic amino acid, are added in step b) of the process for preparing a liquid pharmaceutical composition.
• At least one sugar or one sugar derivative chosen from: sucrose, di- and trisaccharides, polysaccharides, such as dextrose, lactose, maltose, trehalose, cyclodextrins, maltodextrins and dextrans, reducing sugars or polyols, is added in step b) of the process for preparing a liquid pharmaceutical composition.
• a salt chosen from a mineral salt and an organic salt is added in step b).
• the surfactant added in step b) and/or d) is preferably a non-ionic detergent.
• Another subject of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising human immunoglobulin G (IgG) obtained by means of this process, characterized in that the IgG concentration is at least 230 g/l of the composition.
• the IgG concentration is at least 250 g/l of the composition.
• composition according to the invention is advantageously in liquid form.
• the composition according to the invention comprises an amino acid and a surfactant.
• the composition according to the invention comprises an amino acid, a salt and a surfactant.
• the composition according to the invention comprises a sugar or a sugar derivative and a surfactant.
• the composition according to the invention comprises an amino acid, a sugar or a sugar derivative, and a surfactant.
• the composition according to the invention comprises an amino acid, a sugar or a sugar derivative, a salt and a surfactant.
• composition obtained or capable of being obtained by means of the process described herein is also part of the invention.
• compositions are advantageously in a form suitable for subcutaneous or intramuscular administration, preferably subcutaneous administration.
• human immunoglobulin G or “human IgG” in the context of the invention is intended to mean polyvalent immunoglobulins which are essentially IgG, optionally including IgM. They may be whole immunoglobulins, or fragments such as F(ab′)2 or F(ab) and any intermediate fraction obtained during the process for manufacturing the polyvalent immunoglobulins.
• stability corresponds to the physical and/or chemical stability of the IgG.
• physical stability refers to the reduction or absence of formation of insoluble or soluble aggregates of the dimeric, oligomeric or polymeric forms of Ig, and also to the reduction or absence of any structural denaturation of the molecule.
• chemical stability refers to the reduction or absence of any chemical modification of the IgG during storage, in the solid state or in dissolved form, under accelerated conditions. For example, hydrolysis, deamination and/or oxidation phenomena are prevented or delayed. The oxidation of sulphur-containing amino acids is limited.
• step b) the inventors have discovered that adding surfactant before the ultrafiltration, and preferably fractionating the surfactant between step b) and step d), makes it possible to avoid immunoglobulin degradation.
• the liquid IgG compositions signify aqueous solutions of IgG compositions, directly obtained by fractionation of human plasma.
• the aqueous medium is composed of water for injection (WFI) which can contain pharmaceutically acceptable excipients compatible with IgG.
• WFI water for injection
• the IgG compositions can beforehand undergo specific virus inactivation/elimination steps, such as detergent solvent treatment, pasteurization and/or nanofiltration.
• the composition according to the invention comprises IgG which may be polyclonal or monoclonal.
• the IgG can be isolated from human or animal blood or produced by other means, for example by molecular biology techniques, for example in cell systems well known to those skilled in the art.
• the composition according to the invention is particularly suitable for highly purified IgG.
• the IgG of the present invention are obtained by fractionation of human plasma.
• Preferred methods for fractionation of human plasma are described by Cohn et al. (J. Am. Chem. Soc., 68, 459, 1946), Kistler et al. (Vox Sang., 7, 1962, 414-424), Steinbuch et al. (Rev. Franç. Et. Clin. et Biol., XIV, 1054, 1969) and in patent application WO 94/9334, these documents being incorporated as a whole by way of reference.
• a method for preparing an immunoglobulin G composition is also described in patent application WO 02/092632, incorporated as a whole by way of reference.
• the IgG concentrates are generally subjected to a subsequent step of concentration by tangential ultrafiltration, and then to a sterilizing filtration, and can be packaged in bottles and preferably stored at temperatures of around 4° C.
• the IgG of the present invention can be depleted of anti-A antibodies and anti-B antibodies as indicated in patent application WO 2007/077365.
• the step of concentration by tangential ultrafiltration according to the invention makes it possible to achieve an immunoglobulin concentration of at least 230 g/l, preferably at least 250 g/l, without causing clogging of the membrane, the integrity of the immunoglobulins being maintained while at the same time avoiding aggregation at the interfaces and denaturation under the flow or shear-effect stresses.
• the choice of the excipients is based on their stabilizing capacity and their capacity to allow concentration of the IgG during the tangential ultrafiltration step.
• the excipients are added in the following way:
• Excipients which are at least one amino acid and/or at least one surfactant are added to a human immunoglobulin G preparation purified from a plasma fraction of human blood.
• the surfactant(s) is (are) added at a concentration below the critical micellar concentration of said surfactants;
• a surfactant which may be identical to or different from the surfactant that will be added in step b), is added in order to obtain the pharmaceutical composition desired.
• the ultrafiltration step is a tangential ultrafiltration step, for example on a membrane with a cutoff threshold of less than 150 kD.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids, and/or one or more surfactants, and optionally one or more salts.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids and a surfactant.
• excipients which comprise or consist of one or more sugars or sugar derivatives are also added to the IgG preparation before ultrafiltration.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids and one or more sugars or sugar derivatives and a surfactant.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids and one or more sugars or sugar derivatives and one or more salts.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids and one or more sugars or sugar derivatives, one or more salts and a surfactant.
• the Applicant has shown, surprisingly, that highly concentrated IgG can be obtained by formulating the latter before the IgG concentration step by ultrafiltration, by virtue of the addition of an amino acid and/or of a surfactant, typically at a concentration below the critical micellar concentration of said surfactant, so as to ensure, firstly, the obtaining of the preparation directly with the required IgG formulation and, secondly, the stability, compatibility and good tolerance of the pharmaceutical composition, additionally avoiding clogging phenomena at the ultrafiltration membrane.
• the amino acids which can be added during step b) of the process according to the invention are selected from the following group: a hydrophilic amino acid or an amino acid bearing a positively charged side chain, and optionally also at least one hydrophobic amino acid.
• the hydrophilic (or polar) amino acids or the amino acids bearing a positively charged side chain include lysine, arginine, histidine, glycine, serine, threonine, tyrosine, asparagine and glutamine
• hydrophilic amino acids or amino acids bearing a positively charged side chain use may preferentially be made of glycine or histidine.
• hydrophilic amino acid or amino acid bearing a positively charged side chain such as arginine
• hydrophobic amino acid or even of a salt of an alkali or alkaline-earth metal, or of a transition metal promotes the stabilization of the human IgG.
• hydrophobic amino acids include in particular the following amino acids: alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, proline, etc.
• the amino acid of step b) is glycine, preferably at a concentration of from 200 to 300 mM.
• sugars or sugar derivatives which can be added during step b) of the process according to the invention are selected from the following group: sucrose, di- and trisaccharides and polysaccharides, such as dextrose, lactose, maltose, trehalose, cyclodextrins, maltodextrins and dextrans, reducing sugars or polyols.
• reducing sugar mention may in particular be made of glucose or fructose.
• polyol mention may in particular be made of mannitol, sorbitol and xylitol.
• salt is intended to mean a salt of an alkali or alkaline-earth metal or of a transition metal.
• the salts which can be added during step b) of the process according to the invention are selected from the following group: mineral salts, organic salts or a mixture of several salts. Mention may in particular be made, as mineral salts, of: sodium phosphate, sodium chloride, calcium chloride or zinc chloride.
• the salt used is an organic salt, preferably sodium acetate.
• step b from 0 to 100 mM of sodium acetate is added in step b).
• Step b) of the process according to the invention may comprise the addition of one or more surfactants, for example of non-ionic detergent type, said surfactant being added during this step at a concentration below the critical micellar concentration.
• a suitable surfactant used in the composition according to the invention is advantageously chosen from polysorbate 80 (or Tween® 80 which is polyoxyethylene sorbitan monooleate), polysorbate 20 (or Tween® 20 which is polyoxyethylene sorbitan monolaurate), Triton® X 100 (octoxinol 10), poloxamers, polyoxyethylene alkyl ethers, a block copolymer of ethylene/polypropylene and Pluronic®F68 (polyethylene polypropylene glycol).
• Tween® 80, Tween® 20 and poloxamer 188 are used.
• the non-ionic detergents can also be combined with one another.
• the pH of the pharmaceutical composition is adjusted during step b) of the process according to the invention.
• the pH is adjusted between 4.0 and 8.0, advantageously between 4.2 and 5.5 or between 6.8 and 7.8.
• the pH of the liquid pharmaceutical composition is between 6.9 and 7.6, preferably between 7.0 and 7.6, preferably between 7.1 and 7.5, preferably between 7.2 and 7.4 and preferably 7.3.
• Step d) of the process according to the invention may comprise one or more surfactants, for example of non-ionic detergent type.
• a suitable surfactant used in the composition according to the invention is advantageously chosen from polysorbate 80 (or Tween® 80 which is polyoxyethylene sorbitan monooleate), polysorbate 20 (or Tween® 20 which is polyoxyethylene sorbitan monolaurate), Triton® X 100 (octoxinol 10), poloxamers, polyoxyethylene alkyl ethers, a block copolymer of ethylene/polypropylene and Pluronic® F68 (polyethylene polypropylene glycol).
• Tween® 80, Tween® 20 and the poloxamer 188 are used.
• the non-ionic detergents can also be combined with one another.
• concentration of non-ionic detergent sufficient to stabilize the composition according to the invention is preferably between 0 and 1000 ppm, preferably between 0 and 300 ppm, preferably between 0 and 50 ppm.
• the addition of the surfactant in step d makes it possible to avoid the phenomenon of aggregation of the composition.
• the surfactant is a polysorbate, preferably polysorbate 20 or polysorbate 80.
• the surfactant is added in steps b) and/or d), at a total concentration of from 50 to 300 ppm.
• the surfactant is added in step b) at a concentration of less than 75 ppm, preferably less than 50 ppm, and preferably less than 40 ppm.
• the ultrafiltration of step c) can therefore be carried out at a temperature of less than 30° C., preferably less than 25° C.
• the ultrafiltration of step c) is carried out at a temperature of between 15° C. and 25° C., preferably approximately 20° C.
• the process according to the invention makes it possible to obtain a liquid pharmaceutical composition characterized in that the IgG concentration is at least 230 g/l in the composition, preferably at least 250 g/l, typically between 230 g/l and 350 g/l, in said composition.
• the liquid pharmaceutical composition according to the invention comprises at least 230 g/l of immunoglobulin G, it preferably comprises 250 g/l of immunoglobulin G.
• the liquid pharmaceutical composition may also comprise an amino acid and a surfactant.
• the liquid pharmaceutical composition may comprise one or more hydrophilic amino acids or amino acids bearing a positively charged side chain, and optionally also at least one hydrophobic amino acid and a surfactant.
• the liquid pharmaceutical composition may also comprise an amino acid, a salt and a surfactant.
• the liquid pharmaceutical composition may also comprise a sugar or a sugar derivative and a surfactant.
• the liquid pharmaceutical composition may also comprise an amino acid, a sugar or a sugar derivative and a surfactant.
• the liquid pharmaceutical composition may also comprise an amino acid, a sugar or a sugar derivative, a salt and a surfactant.
• the invention provides an immunoglobulin G composition comprising at least one amino acid, at least one surfactant, and optionally at least one salt, characterized in that the immunoglobulin G concentration is at least 230 g/l.
• the composition comprises an amino acid, a salt and a surfactant.
• the composition comprises:
• the invention provides an immunoglobulin G composition comprising at least one amino acid, at least one salt and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g/l.
• the immunoglobulin G concentration is at least approximately 250 g/l approximately and the composition comprises an amino acid, a salt and a surfactant.
• the composition comprises:
• composition may comprise:
• the composition comprises:
• the composition comprises:
• the composition comprises:
• the invention provides an immunoglobulin G comprising at least one amino acid and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g/l.
• the immunoglobulin G concentration is at least approximately 250 g/l and the composition comprises an amino acid and a surfactant.
• a preferred liquid pharmaceutical composition according to the invention comprises:
• composition comprises:
• composition comprises:
• Another preferred composition comprises:
• composition comprises:
• the composition comprises:
• the invention provides an immunoglobulin G composition comprising at least one amino acid, at least one sugar or one sugar derivative and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g/l.
• the immunoglobulin G concentration is at least approximately 250 g/l and the composition comprises an amino acid, a sugar and a surfactant, the pH of the solution being between 4.2 and 5.5.
• an immunoglobulin G composition comprising at least one sugar or one sugar derivative and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g/l.
• the immunoglobulin G concentration is at least 250 g/l and the composition comprises a sugar and a surfactant.
• composition described herein comprises:
• the invention provides an immunoglobulin G composition comprising at least one amino acid, at least one salt and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g/l.
• the immunoglobulin G concentration is 270 g/l and the composition comprises an amino acid, a salt and a surfactant.
• the composition comprises:
• the only excipients of the IgG composition according to the invention are said amino acids, salt and surfactant (preferably of non-ionic detergent type).
• Such an IgG composition exclusively consisting of these excipients (in addition to the IgG) has the advantage of providing good stability, good compatibility and good local tolerance of the IgG compositions and also a reduction in the industrial-scale preparation times and costs by virtue of the presence of a minimal effective number of excipients and also the presence of a minimal effective amount of excipients.
• the IgG composition of the invention is of use in therapy, and in particular in a form that is injectable, not only intravenously, but also more advantageously subcutaneously or intramuscularly.
• the subcutaneous route for the treatment of chronic autoimmune diseases has several advantages, such as the improvement of patient comfort and a decrease in side effects.
• Subcutaneous administration does not require venous access, thereby constituting, in certain cases, a decisive advantage when the absence of a venous approach blocks access to the treatment, in particular for young children.
• immunoglobulins via the subcutaneous route also reduces certain side effects associated with intravenous infusions, in particular the risk of systemic reactions.
• the large variations in circulating titres observed by the intravenous route are avoided, allowing better regulation of the serum titre in the physiological range between infusions.
• the immunoglobulins administered subcutaneously (SCIg) have an efficacy that is at least equivalent to immunoglobulins administered intravenously (IVIg).
• the increase in the concentration contributes to patient comfort by reducing the frequency of injection.
• the SCIg concentration is a determining characteristic which conditions the injection volume and number of injection sites and, consequently, the frequency of administration.
• the IgG composition of the invention in liquid form, after storage for a period of 6 months at 25° C., has a level of polymers well below the standards set by the European Pharmacopoeia (3%), advantageously less than approximately 1%.
• composition of the invention may be a pharmaceutical composition, i.e. a composition suitable for therapeutic use.
• the pharmaceutical composition of the invention is thus of use as a medicament, in particular in order to treat primary immune deficiencies with an antibody production defect, Kawasaki disease, childhood and adult immune thrombocytopaenic purpura, secondary immune deficiencies with an antibody production defect, in particular chronic lymphoid leukaemia or myeloma that are associated with recurrent infections, HIV infection of children associated with bacterial infections, multifocal motor neuropathies, Guillain-Barré syndrome, chronic or severe acute Parvovirus B19 infections, acquired or constitutional immunodeficiency, cortico-resistant dermatomyositis, acute myasthenia, chronic idiopathic polyradiculoneuritis, immune thrombocytopaenic purpura, for example associated with HIV infection, stiff-person syndrome, autoimmune neutropaenia, resistant autoimmune erythroblastopaenia, autoantibody-induced acquired anticoagulant syndrome, rheumatoid arthritis, uveitis.
• primary immune deficiencies with an antibody production defect Kawasaki disease
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition 150 mM of glycine and 50 mM of acetate buffer (25 mM of sodium acetate and 25 mM of acetic acid) are added to the IgG composition obtained and the preformulated IgG composition is subjected to tangential ultrafiltration on a cassette at a pH between 4.6 and 5. 200 ppm of Tween 80 are then added and the formulated and concentrated IgG composition at 250 g/l is obtained.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition 150 mM of glycine and 50 mM of acetate buffer (25 mM of sodium acetate and 25 mM of acetic acid) are added to the IgG composition obtained and the preformulated IgG composition is subjected to tangential ultrafiltration on a cassette at a pH between 4.6 and 5. 200 ppm of poloxamer are then added and the formulated and concentrated IgG composition at 250 g/l is obtained.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition 150 mM of glycine and 50 mM of acetate buffer (25 mM of sodium acetate and 25 mM of acetic acid) are added to the IgG composition obtained and the preformulated IgG composition is subjected to tangential ultrafiltration on a cassette at a pH between 4.6 and 5. The formulated and concentrated IgG composition at 250 g/l is thus obtained.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition 150 mM of proline and 50 mM of acetate buffer (25 mM of sodium acetate and 25 mM of acetic acid) are added to the IgG composition obtained and the preformulated IgG composition is subjected to tangential ultrafiltration on a cassette at a pH between 4.6 and 5. 200 ppm of Tween 80 are then added and the formulated and concentrated IgG composition at 250 g/l is thus obtained.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• IgG composition was obtained according to the method developed by the Applicant in international patent application WO 2007/077365.
• 250 mM of glycine are added to the IgG composition obtained and the preformulated IgG composition is subjected to tangential ultrafiltration on a cassette at a pH between 4.5 and 5.5. 200 ppm of Tween 80 are then added and the formulated and concentrated IgG composition at 250 g/l is obtained.
• a 10% IgG solution (obtained according to the method developed by the Applicant in international patent application WO 2007/077365 or WO 02/092632), the composition of which is given in detail in Table 2 below, is used as a control.
• Protein aggregates or exogenous particles with a diameter greater than approximately 50 ⁇ m are visible to the naked eye.
• the bottles are held to a beam of white light by three different operators who note the presence or absence of visible particles.
• the particles with a diameter greater than 10 ⁇ m and 25 ⁇ m are quantified by the light obscuration method (Light Obscuration; on a Particle Measuring Systems Inc. instrument, Model LS-200) adapted from the European Pharmacopoeia 6th edition, ⁇ 2.9.19, method 1B: the samples are diluted by a factor of 2 with water for injection filtered through 0.22 ⁇ m just before analysis in order to reduce the viscosity on the product; 5 ml of diluted product are used for the rinsing and 5 ml for the measurement.
• the light obscuration method Light Obscuration; on a Particle Measuring Systems Inc. instrument, Model LS-200
• DLS makes it possible to measure the hydrodynamic diameters of proteins and of aggregates present in solution. This measurements makes it possible to follow aggregation phenomena at early stages of formation, since the accessible sizes range from a nanometer to a micron.
• the measurement was carried out using a scattering bench (ALV/CGS-3 Compact Goniometer System) from ALV at an angle of 90°.
• 0.04 M of NaCl were added to all the solutions in order to maintain a sufficient ionic strength and to enable a coherent size measurement.
• the immunoglobulin fragmentation is quantified by HP-SEC.
• compositions F1, F2 and F6 are much higher than those measured in the compositions containing surfactants (F3, F4, F5 and F7), which clearly shows the importance of the presence of surfactants.
• the compositions containing surfactants F3, F4, F5 and F7 remain free of visible particles and exhibit fewer sub-visible particles than compositions F1, F2 and F6.
• the polymer level detected is below the standards imposed by the pharmacopoeia ( ⁇ 3%) for all the compositions.
• the fragmentation level is comparable to the 10% IgG reference product.
• composition F4 The study of local tolerance was carried out on three animals treated by simultaneous subcutaneous administration of composition F4, of 10% IgNG, of Subcuvia® (160 g/l or 16% IgG, from Baxter) and a glycine-acetate-Tween 80 formulation buffer, at a flow rate of 10 ml/h.
• the infusion volume was fixed at 10 ml.
• a 27 G needle was used.
• the injection sites were randomized from one animal to the other.
• composition F4 is considered to be satisfactory.

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• 2010
  • 2010-07-19 FR FR1055825A patent/FR2962650B1/fr not_active Expired - Fee Related
• 2011
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